Conditional membrane proteins associate with membranes in response to binding specific ligands. We report the application of NMR techniques to gain insight into the structure, dynamics, and protein-membrane interactions of two fundamentally different conditional membrane modules: C1 and C2 domains, both from the Protein Kinase Ca (PKCa), that are covalently linked to one another in the primary structure of the parent protein. Using NMR relaxation dispersion techniques, paramagnetic relaxation enhancement (PRE) experiments, and NMR-detected ligand binding studies, we demonstrate the role of conformational plasticity and initial membrane pre-association in modulating the affinity of the C1 domain to its natural cofactor, diacylglycerol. We show that the C2 domain employs a drastically different mechanism of membrane insertion that involves modulation of its electrostatic potential by divalent metal ions. The dynamics of loop and N- and C-terminal regions of C2 changes as a function of metal ligation state, suggesting a possible mechanism for propagating the information about the metal-binding event to other PKCa domains. In aggregate, our studies provide a view of conditional membrane domains as highly dynamic entities, in which conformational plasticity and synergistic action of cytosolic and membrane-embedded ligands define their nuanced signaling response. The functional and structural interplay between C1 and C2 domains will also be discussed in the context of the only two existing multi-domain structures of Protein Kinase C, one of which came from our laboratory.